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ELife Apr 2022Male infertility is an important health concern that is expected to have a major genetic etiology. Although high-throughput sequencing has linked gene defects to more...
Male infertility is an important health concern that is expected to have a major genetic etiology. Although high-throughput sequencing has linked gene defects to more than 50% of rare and severe sperm anomalies, less than 20% of common and moderate forms are explained. We hypothesized that this low success rate could at least be partly due to oligogenic defects - the accumulation of several rare heterozygous variants in distinct, but functionally connected, genes. Here, we compared fertility and sperm parameters in male mice harboring one to four heterozygous truncating mutations of genes linked to multiple morphological anomalies of the flagellum (MMAF) syndrome. Results indicated progressively deteriorating sperm morphology and motility with increasing numbers of heterozygous mutations. This first evidence of oligogenic inheritance in failed spermatogenesis strongly suggests that oligogenic heterozygosity could explain a significant proportion of asthenoteratozoospermia cases. The findings presented pave the way to further studies in mice and man.
Topics: Abnormalities, Multiple; Asthenozoospermia; Humans; Infertility, Male; Male; Multifactorial Inheritance; Mutation; Sperm Tail; Spermatozoa
PubMed: 35451961
DOI: 10.7554/eLife.75373 -
Molecular Psychiatry Jan 2022During the past decade, polygenic scores have become a fast-growing area of research in the behavioural sciences. The ability to directly assess people's genetic... (Review)
Review
During the past decade, polygenic scores have become a fast-growing area of research in the behavioural sciences. The ability to directly assess people's genetic propensities has transformed research by making it possible to add genetic predictors of traits to any study. The value of polygenic scores in the behavioural sciences rests on using inherited DNA differences to predict, from birth, common disorders and complex traits in unrelated individuals in the population. This predictive power of polygenic scores does not require knowing anything about the processes that lie between genes and behaviour. It also does not mandate disentangling the extent to which the prediction is due to assortative mating, genotype-environment correlation, or even population stratification. Although bottom-up explanation from genes to brain to behaviour will remain the long-term goal of the behavioural sciences, prediction is also a worthy achievement because it has immediate practical utility for identifying individuals at risk and is the necessary first step towards explanation. A high priority for research must be to increase the predictive power of polygenic scores to be able to use them as an early warning system to prevent problems.
Topics: Brain; Genome-Wide Association Study; Genotype; Humans; Multifactorial Inheritance; Phenotype
PubMed: 34686768
DOI: 10.1038/s41380-021-01348-y -
ELife Mar 2019Great care is needed when interpreting claims about the genetic basis of human variation based on data from genome-wide association studies.
Great care is needed when interpreting claims about the genetic basis of human variation based on data from genome-wide association studies.
Topics: Biological Specimen Banks; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Selection, Genetic; United Kingdom
PubMed: 30895925
DOI: 10.7554/eLife.45380 -
Genes Jul 2023Heterozygous carriers of pathogenic/likely pathogenic variants in autosomal recessive disorders seem to be asymptomatic. However, in recent years, an increasing number... (Review)
Review
Heterozygous carriers of pathogenic/likely pathogenic variants in autosomal recessive disorders seem to be asymptomatic. However, in recent years, an increasing number of case reports have suggested that mild and unspecific symptoms can occur in some heterozygotes, as symptomatic heterozygotes have been identified across different disease types, including neurological, neuromuscular, hematological, and pulmonary diseases. The symptoms are usually milder in heterozygotes than in biallelic variants and occur "later in life". The status of symptomatic heterozygotes as separate entities is often disputed, and alternative diagnoses are considered. Indeed, often only a thin line exists between dual, dominant, and recessive modes of inheritance and symptomatic heterozygosity. Interestingly, recent population studies have found global disease effects in heterozygous carriers of some genetic variants. What makes the few heterozygotes symptomatic, while the majority show no symptoms? The molecular basis of this phenomenon is still unknown. Possible explanations include undiscovered deep-splicing variants, genetic and environmental modifiers, digenic/oligogenic inheritance, skewed methylation patterns, and mutational burden. Symptomatic heterozygotes are rarely reported in the literature, mainly because most did not undergo the complete diagnostic procedure, so alternative diagnoses could not be conclusively excluded. However, despite the increasing accessibility to high-throughput technologies, there still seems to be a small group of patients with mild symptoms and just one variant of autosomes in biallelic diseases. Here, we present some examples, the current state of knowledge, and possible explanations for this phenomenon, and thus argue against the existing dominant/recessive classification.
Topics: Humans; Heterozygote; Inheritance Patterns; Knowledge; Multifactorial Inheritance; Protein Processing, Post-Translational
PubMed: 37628614
DOI: 10.3390/genes14081562 -
Journal of Atherosclerosis and... Dec 2020
Topics: Gene-Environment Interaction; Genetic Predisposition to Disease; Genetic Variation; Humans; Hypertriglyceridemia; Multifactorial Inheritance; Mutation
PubMed: 32493883
DOI: 10.5551/jat.ED133 -
Current Psychiatry Reports Aug 2017We will describe the success of recent genome-wide association studies that identify genetic variants associated with depression and outline the strategies used to... (Review)
Review
PURPOSE OF REVIEW
We will describe the success of recent genome-wide association studies that identify genetic variants associated with depression and outline the strategies used to reduce heterogeneity and increase sample size.
RECENT FINDINGS
The CONVERGE consortium identified two genetic associations by focusing on a sample of Chinese women with recurrent severe depression. Three other loci have been found in Europeans by combining cohorts with clinical diagnosis and measures of depressive symptoms to increase sample size. 23andMe identified 15 loci associated with depression using self-report of clinical diagnosis in a study of over 300,000 individuals. The first genetic associations with depression have been identified, and this number is now expected to increase linearly with sample size, as seen in other polygenic disorders. These loci provide invaluable insights into the biology of depression and exciting opportunities to develop new biomarkers and therapeutic targets.
Topics: Depression; Depressive Disorder, Major; Genetic Variation; Genome-Wide Association Study; Humans; Multifactorial Inheritance; White People
PubMed: 28608123
DOI: 10.1007/s11920-017-0803-9 -
International Journal of Obesity (2005) Jun 2024The genetic architecture of extreme non-syndromic obesity in adults remains to be elucidated. A range of genes are known to cause monogenic obesity, but even when...
BACKGROUND/OBJECTIVE
The genetic architecture of extreme non-syndromic obesity in adults remains to be elucidated. A range of genes are known to cause monogenic obesity, but even when pathogenic mutations are present, there may be variable penetrance.
METHODS
Whole-exome sequencing (WES) was carried out on a 15-year-old male proband of Pakistani ancestry who had severe obesity. This was followed by family segregation analysis, using Sanger sequencing. We also undertook re-analysis of WES data from 91 unrelated adults with severe obesity (86% white European ancestry) from the Personalised Medicine for Morbid Obesity (PMMO) cohort, recruited from the UK National Health Service.
RESULTS
We identified an oligogenic mode of inheritance of obesity in the proband's family-this provided the impetus to reanalyze existing sequence data in a separate dataset. Analysis of PMMO participant data revealed two further patients who carried more than one rare, predicted-deleterious mutation in a known monogenic obesity gene. In all three cases, the genes involved had known autosomal dominant inheritance, with incomplete penetrance.
CONCLUSION
Oligogenic inheritance may explain some of the variable penetrance in Mendelian forms of obesity. We caution clinicians and researchers to avoid confining sequence analysis to individual genes and, in particular, not to stop looking when the first potentially-causative mutation is found.
Topics: Humans; Male; Adolescent; Obesity, Morbid; Adult; Exome Sequencing; Pedigree; Female; Genetic Predisposition to Disease; Mutation; Penetrance; United Kingdom; Pakistan; Multifactorial Inheritance
PubMed: 38297031
DOI: 10.1038/s41366-024-01476-9 -
Immunology Sep 2018High-throughput sequencing of the DNA/RNA encoding antibody heavy- and light-chains is rapidly transforming the field of adaptive immunity. It can address key questions,... (Review)
Review
High-throughput sequencing of the DNA/RNA encoding antibody heavy- and light-chains is rapidly transforming the field of adaptive immunity. It can address key questions, including: (i) how the B-cell repertoire differs in health and disease; and (ii) if it does differ, the point(s) in B-cell development at which this occurs. The advent of technologies, such as whole-genome sequencing, offers the chance to link abnormalities in the B-cell antibody repertoire to specific genomic variants and polymorphisms. Here, we discuss the current research using B-cell antibody repertoire sequencing in three polygenic autoimmune diseases where there is good evidence for a pathological role for B-cells, namely systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. These autoimmune diseases exhibit significantly skewed B-cell receptor repertoires compared with healthy controls. Interestingly, some common repertoire defects are shared between diseases, such as elevated IGHV4-34 gene usage. B-cell clones have effectively been characterized and tracked between different tissues and blood in autoimmune disease. It has been hypothesized that these differences may signify differences in B-cell tolerance; however, the mechanisms and implications of these defects are not clear.
Topics: Antibodies; Autoimmune Diseases; High-Throughput Nucleotide Sequencing; Humans; Multifactorial Inheritance
PubMed: 29574826
DOI: 10.1111/imm.12927 -
Brain : a Journal of Neurology Jan 2019Holoprosencephaly is a pathology of forebrain development characterized by high phenotypic heterogeneity. The disease presents with various clinical manifestations at...
Holoprosencephaly is a pathology of forebrain development characterized by high phenotypic heterogeneity. The disease presents with various clinical manifestations at the cerebral or facial levels. Several genes have been implicated in holoprosencephaly but its genetic basis remains unclear: different transmission patterns have been described including autosomal dominant, recessive and digenic inheritance. Conventional molecular testing approaches result in a very low diagnostic yield and most cases remain unsolved. In our study, we address the possibility that genetically unsolved cases of holoprosencephaly present an oligogenic origin and result from combined inherited mutations in several genes. Twenty-six unrelated families, for whom no genetic cause of holoprosencephaly could be identified in clinical settings [whole exome sequencing and comparative genomic hybridization (CGH)-array analyses], were reanalysed under the hypothesis of oligogenic inheritance. Standard variant analysis was improved with a gene prioritization strategy based on clinical ontologies and gene co-expression networks. Clinical phenotyping and exploration of cross-species similarities were further performed on a family-by-family basis. Statistical validation was performed on 248 ancestrally similar control trios provided by the Genome of the Netherlands project and on 574 ancestrally matched controls provided by the French Exome Project. Variants of clinical interest were identified in 180 genes significantly associated with key pathways of forebrain development including sonic hedgehog (SHH) and primary cilia. Oligogenic events were observed in 10 families and involved both known and novel holoprosencephaly genes including recurrently mutated FAT1, NDST1, COL2A1 and SCUBE2. The incidence of oligogenic combinations was significantly higher in holoprosencephaly patients compared to two control populations (P < 10-9). We also show that depending on the affected genes, patients present with particular clinical features. This study reports novel disease genes and supports oligogenicity as clinically relevant model in holoprosencephaly. It also highlights key roles of SHH signalling and primary cilia in forebrain development. We hypothesize that distinction between different clinical manifestations of holoprosencephaly lies in the degree of overall functional impact on SHH signalling. Finally, we underline that integrating clinical phenotyping in genetic studies is a powerful tool to specify the clinical relevance of certain mutations.
Topics: Case-Control Studies; Comparative Genomic Hybridization; Exome; Female; Holoprosencephaly; Humans; Male; Multifactorial Inheritance; Mutation; Pedigree; Phenotype; Rare Diseases
PubMed: 30508070
DOI: 10.1093/brain/awy290 -
Nature Human Behaviour Sep 2023Personality and cognitive function are heritable mental traits whose genetic foundations may be distributed across interconnected brain functions. Previous studies have...
Personality and cognitive function are heritable mental traits whose genetic foundations may be distributed across interconnected brain functions. Previous studies have typically treated these complex mental traits as distinct constructs. We applied the 'pleiotropy-informed' multivariate omnibus statistical test to genome-wide association studies of 35 measures of neuroticism and cognitive function from the UK Biobank (n = 336,993). We identified 431 significantly associated genetic loci with evidence of abundant shared genetic associations, across personality and cognitive function domains. Functional characterization implicated genes with significant tissue-specific expression in all tested brain tissues and brain-specific gene sets. We conditioned independent genome-wide association studies of the Big 5 personality traits and cognitive function on our multivariate findings, boosting genetic discovery in other personality traits and improving polygenic prediction. These findings advance our understanding of the polygenic architecture of these complex mental traits, indicating a prominence of pleiotropic genetic effects across higher order domains of mental function such as personality and cognitive function.
Topics: Humans; Genome-Wide Association Study; Personality; Phenotype; Multifactorial Inheritance; Cognition
PubMed: 37365406
DOI: 10.1038/s41562-023-01630-9